The long-term goal of the proposed research is to optimize the efficacy of antiretroviral agents through pharmacologically - and virologically - directed therapy. The applicants have shown that concentration - controlled zidovudine therapy is feasible, safe, and significantly reduces pharmacokinetic variability. Furthermore, the CD4 cell response was significantly better and heterogenicity was reduced compared with standard dose therapy. In this renewal application, the applicants propose to continue to understand and control pharmacokinetic variability and therapy. Since there is no "gold- standard" combination regimen, the applicants have chosen the nucleoside agents zidovudine and lamivudine (3TC), and the HIV protease inhibitor, indinavir, as the drugs of interest. The applicants will determine the safety and feasibility of simultaneous concentration- controlled combination therapy with all three, and evaluate whether this approach, contrasted to standard-dose combination therapy, can achieve and maintain a sustained anti-HIV effect. The intracellular clinical pharmacology of zidovudine and lamivudine will be investigated to determine if triphosphate moieties more precisely predict antiviral efficacy. The study design is simple and elegant. It is randomized, controlled, sample-size efficient, not subject to bias, and powered to produce clinically meaningful results that can be applied to routine patient management.